Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Changes in folate metabolism are correlated tumor formation and birth defects. Folate genes are also involved in the methylation of DNA and proper brain function. . We are searching for genetic variants in genes related to folate, methionine and homocysteine metabolism. Individuals affected with cancer or spina bifida (one form of neural tube defects) will be tested for these variants. Variants found at higher frequency in individuals with disease will help us identify genes associated with risk. In the past year we have tested more than 10 genes for variants that might perturb folate metabolism and therefore be associated with an increase risk of having a child with an neural tube defect. As expected, we have been able to rule out the majority of these variants as risk factor by screening more than two hundred spina bifida families. Two new risk factors were identified for neural tube defects. Families carrying specific variants in these folate related genes have a two-fold risk of having a child with spina bifida. These previously un-described variants may be responsible for up to 30% of all neural tube defects. Approximately one in five individuals in the population carry one of these risk factors. We have re-created these genes in the laboratory and are currently using an experimental system to determine exactly how these variants alter the function of these proteins. A detailed knowledge of the function of these two genes will add to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.